Research Article| Volume 141, ISSUE 3, P454-460, June 2016

Download started.


The influence of clinical and genetic factors on patient outcome in small cell carcinoma of the ovary, hypercalcemic type


      • All SCCOHT patients should undergo genetic testing for germline SMARCA4 mutations.
      • HDC-aSCR may offer SCCOHT patients the best outcome, and should be studied further.



      Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive tumor, with long term survival at ~30% in early stage disease. SCCOHT is caused by germline and somatic SMARCA4 mutations, but the effect of the mutation type on patients remains unknown. Furthermore, the rarity of SCCOHT has resulted in varied treatment, with no standardized protocols. We analyzed 293 cases to determine the effect of treatment modalities and SMARCA4 mutations on patient diagnosis and outcome.


      In 293 SCCOHT patients we collected information on age and stage at diagnosis, treatment modality (surgery, chemotherapy, radiotherapy, and/or high-dose chemotherapy with autologous stem cell rescue (HDC-aSCR)), SMARCA4 mutation origin (germline/somatic), and overall survival. Cox analysis and log-rank tests were performed on 257 cases with available survival data.


      The strongest prognostic factors were stage at diagnosis (p = 2.72e‐15) and treatment modality (p = 3.87e‐13). For FIGO stages II–IV, 5-year survival was 71% for patients who received HDC-aSCR, compared to 25% in patients who received conventional chemotherapy alone following surgery (p = 0.002). Patients aged ≥40 had a worse outcome than younger patients (p = 0.04). Twenty-six of 60 tested patients carried a germline SMARCA4 mutation, including all patients diagnosed <15 years; carriers presented at a younger age than non-carriers (p = 0.02).


      Stage at diagnosis is the most significant prognostic factor in SCCOHT and consolidation with HDC-aSCR may provide the best opportunity for long-term survival. The large fraction of SMARCA4 germline mutations carriers warrants genetic counseling for all patients.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Gynecologic Oncology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Scully R.E.
        Tumors of the ovary and maldeveloped gonads.
        in: Hartmann W.H. Cowan W.R. Atlas of Tumor Pathology. Armed Forces Institute of Pathology, Washington, DC1979 (second series, fascicle 16 Ed.)
        • Estel R.
        • Hackethal A.
        • Kalder M.
        • Münstedt K.
        Small cell carcinoma of the ovary of the hypercalcaemic type: an analysis of clinical and prognostic aspects of a rare disease on the basis of cases published in the literature.
        Arch. Gynecol. Obstet. 2011; 284: 1277-1282
        • Callegaro-Filho D.
        • Burke T.W.
        • Eifel P.J.
        • Ramirez P.T.
        • Euscher E.E.
        • Schmeler K.M.
        Radiotherapy for recurrent small cell carcinoma of the ovary: a case report and review of the literature.
        Gynecol. Oncol. Rep. 2015; 11: 23-25
        • Jamy O.
        • Yaghmour G.
        • Hare F.
        • Martin M.G.
        Population-based analysis of the clinical features of primary small cell carcinoma of the ovary.
        Anticancer Res. 2015; 35: 3091-3095
        • Jelinic P.
        • Mueller J.J.
        • Olvera N.
        • Dao F.
        • Scott S.N.
        • Shah R.
        • et al.
        Recurrent SMARCA4 mutations in small cell carcinoma of the ovary.
        Nat. Genet. 2014; 46: 424-426
        • Ramos P.
        • Karnezis A.N.
        • Craig D.W.
        • Sekulic A.
        • Russell M.L.
        • Hendricks W.P.
        • et al.
        Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4.
        Nat. Genet. 2014; 46: 427-429
        • Witkowski L.
        • Carrot-Zhang J.
        • Albrecht S.
        • Fahiminiya S.
        • Hamel N.
        • Tomiak E.
        • et al.
        Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type.
        Nat. Genet. 2014; 46: 438-443
        • Kupryjańczyk J.
        • Dansonka-Mieszkowska A.
        • Moes-Sosnowska J.
        • Plisiecka-Hałasa J.
        • Szafron L.
        • Podgórska A.
        • et al.
        Ovarian small cell carcinoma of hypercalcemic type - evidence of germline origin and SMARCA4 gene inactivation. A pilot study.
        Pol. J. Pathol. 2013; 64: 238-246
        • Witkowski L.
        • Foulkes W.D.
        In brief: picturing the complex world of chromatin remodelling families.
        J. Pathol. 2015; 237: 403-406
        • Bailey S.
        • Murray M.J.
        • Witkowski L.
        • Hook E.
        • Hasselblatt M.
        • Crawford R.
        • et al.
        Biallelic somatic SMARCA4 mutations in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT).
        Pediatr. Blood Cancer. 2015; 62: 728-730
        • Jelinic P.
        • Schlappe B.A.
        • Conlon N.
        • Tseng J.
        • Olvera N.
        • Dao F.
        • et al.
        Concomitant loss of SMARCA2 and SMARCA4 expression in small cell carcinoma of the ovary, hypercalcemic type.
        Mod. Pathol. 2016; 29: 60-66
        • Moes-Sosnowska J.
        • Szafron L.
        • Nowakowska D.
        • Dansonka-Mieszkowska A.
        • Budzilowska A.
        • Konopka B.
        • et al.
        Germline SMARCA4 mutations in patients with ovarian small cell carcinoma of hypercalcemic type.
        Orphanet J. Rare Dis. 2015; 10: 32
        • Rabinovich A.
        • Witkowski L.
        • Shaco-Levi R.
        • Meirovitz M.
        • Hasselblatt M.
        • Foulkes W.D.
        Primary rhabdoid tumor of the ovary: when large cells become small cells.
        Gynecol. Oncol. Rep. 2015; 12: 64-66
        • Ramos P.
        • Karnezis A.N.
        • Hendricks W.P.D.
        • Wang Y.
        • Tembe W.
        • Zismann V.L.
        • et al.
        Loss of the tumor suppressor SMARCA4 in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT).
        Rare Dis. 2014; 2: e967148
        • Brennan B.
        • Stiller C.
        • Bourdeaut F.
        Extracranial rhabdoid tumours: what we have learned so far and future directions.
        Lancet Oncol. 2013; 14: e329-e336
        • Hasselblatt M.
        • Nagel I.
        • Oyen F.
        • Bartelheim K.
        • Russell R.B.
        • Schuller U.
        • et al.
        SMARCA4-mutated atypical teratoid/rhabdoid tumors are associated with inherited germline alterations and poor prognosis.
        Acta Neuropathol. 2014; 128: 453-456
        • Fahiminiya S.
        • Witkowski L.
        • Nadaf J.
        • Carrot-Zhang J.
        • Goudie C.
        • Hasselblatt M.
        • et al.
        Molecular analyses reveal close similarities between small cell carcinoma of the ovary, hypercalcemic type and atypical teratoid/rhabdoid tumor.
        Oncotarget. 2016; 7: 1732-1740
        • Foulkes W.D.
        • Clarke B.A.
        • Hasselblatt M.
        • Majewski J.
        • Albrecht S.
        • McCluggage W.G.
        No small surprise - small cell carcinoma of the ovary, hypercalcaemic type, is a malignant rhabdoid tumour.
        J. Pathol. 2014; 233: 209-214
        • Young R.H.
        • Oliva E.
        • Scully R.E.
        Small cell carcinoma of the ovary, hypercalcemic type. A clinicopathological analysis of 150 cases.
        Am. J. Surg. Pathol. 1994; 18: 1102-1116
        • Harrison M.L.
        • Hoskins P.
        • du Bois A.
        • Quinn M.
        • Rustin G.J.S.
        • Ledermann J.A.
        • et al.
        Small cell of the ovary, hypercalcemic type—analysis of combined experience and recommendation for management. A GCIG study.
        Gynecol. Oncol. 2006; 100: 233-238
        • Idei Y.
        • Kitazawa S.
        • Fujimori T.
        • Ajiki T.
        • Asaka K.
        • Takeuchi S.
        • et al.
        Ovarian small cell carcinoma with K-ras mutation: a case report with genetic analysis.
        Hum. Pathol. 1996; 27: 77-79
        • Saikia U.N.
        • Malhotra P.
        • Khandelwal N.
        • Varma S.
        • Joshi K.
        Small cell carcinoma of the ovary presenting as bone marrow metastasis: a rare presenting feature.
        Indian J. Pathol. Microbiol. 2005; 48: 402-404
        • Berchuck A.
        • Witkowski L.
        • Hasselblatt M.
        • Foulkes W.D.
        Prophylactic oophorectomy for hereditary small cell carcinoma of the ovary, hypercalcemic type.
        Gynecol. Oncol. Rep. 2015; 12: 20-22
        • Martinez-Borges A.R.
        • Petty J.K.
        • Hurt G.
        • Stribling J.T.
        • Press J.Z.
        • Castellino S.M.
        Familial small cell carcinoma of the ovary.
        Pediatr. Blood Cancer. 2009; 53: 1334-1336
        • Le Loarer F.
        • Watson S.
        • Pierron G.
        • de Montpreville V.T.
        • Ballet S.
        • Firmin N.
        • et al.
        SMARCA4 inactivation defines a group of undifferentiated thoracic malignancies transcriptionally related to BAF-deficient sarcomas.
        Nat. Genet. 2015; 47: 1200-1205
        • Lavrut P.-M.
        • Le Loarer F.
        • Normand C.
        • Grosos C.
        • Dubois R.
        • Buenerd A.
        • et al.
        Small cell carcinoma of the ovary, hypercalcemic type/ovarian malignant rhabdoid tumor: report of a bilateral case in a teenager associated with SMARCA4 germline mutation.
        Pediatr. Dev. Pathol. 2015;
        • Stuckey A.R.
        • Onstad M.A.
        Hereditary breast cancer: an update on risk assessment and genetic testing in 2015.
        Am. J. Obstet. Gynecol. 2015; 213: 161-165
        • Distelmaier F.
        • Calaminus G.
        • Harms D.
        • Sträter R.
        • Kordes U.
        • Fleischhack G.
        • et al.
        Ovarian small cell carcinoma of the hypercalcemic type in children and adolescents.
        Cancer. 2006; 107: 2298-2306
        • Pressey J.G.
        • Kelly D.R.
        • Hawthorne H.T.
        Successful treatment of preadolescents with small cell carcinoma of the ovary hypercalcemic type.
        J. Pediatr. Hematol. Oncol. 2013; 35: 566-569
        • Pautier P.
        • Ribrag V.
        • Duvillard P.
        • Rey A.
        • Elghissassi I.
        • Sillet-Bach I.
        • et al.
        Results of a prospective dose-intensive regimen in 27 patients with small cell carcinoma of the ovary of the hypercalcemic type.
        Ann. Oncol. 2007; 18: 1985-1989
        • Christin A.A.
        Successful treatment for advanced small cell carcinoma of the ovary.
        Pediatr. Blood Cancer. 2008; 50: 1276-1277
        • Kopp L.M.
        • Desoky S.
        • Pugh J.
        • Herzog C.E.
        Small cell carcinoma of the ovary of the hypercalcemic type presenting in a 5-year-old girl.
        J. Pediatr. Hematol. Oncol. 2013; 35: e217-e218
        • Origoni M.
        Small cell carcinoma of the ovary: report of three cases of a poor prognosis disease.
        J. Med. Cases. 2013; 4: 189
        • Schleef J.
        • Wagner A.
        • Kleta R.
        • Schaarschmidt K.
        • Dockhorn-Dworniczak B.
        • Willital G.H.
        • et al.
        Small-cell carcinoma of the ovary of the hypercalcemic type in an 8-year-old girl.
        Pediatr. Surg. Int. 1999; 15: 431-434
        • Schultz K.A.P.
        • Sencer S.F.
        • Messinger Y.
        • Neglia J.P.
        • Steiner M.E.
        Pediatric ovarian tumors: a review of 67 cases.
        Pediatr. Blood Cancer. 2005; 44: 167-173
        • Woopen H.
        • Sehouli J.
        • Pietzner K.
        • Darb-Esfahani S.
        • Braicu E.I.
        • Fotopoulou C.
        Clinical experience of young patients with small cell ovarian carcinoma of the hypercalcemic type (OSCCHT).
        Eur. J. Obstet. Gynecol. Reprod. Biol. 2012; 165: 313-317
        • Benesch M.
        • Bartelheim K.
        • Fleischhack G.
        • Gruhn B.
        • Schlegel P.G.
        • Witt O.
        • et al.
        High-dose chemotherapy (HDCT) with auto-SCT in children with atypical teratoid/rhabdoid tumors (AT/RT): a report from the European Rhabdoid Registry (EU-RHAB).
        Bone Marrow Transplant. 2014; 49: 370-375
        • Lafay-Cousin L.
        • Hawkins C.
        • Carret A.S.
        • Johnston D.
        • Zelcer S.
        • Wilson B.
        • et al.
        Central nervous system atypical teratoid rhabdoid tumours: the Canadian Paediatric Brain Tumour Consortium experience.
        Eur. J. Cancer. 2012; 48: 353-359
        • Lau C.S.M.
        • Mahendraraj K.
        • Chamberlain R.S.
        Atypical teratoid rhabdoid tumors: a population-based clinical outcomes study involving 174 patients from the Surveillance, Epidemiology, and End Results database (1973–2010).
        Cancer Manag. Res. 2015; 7: 301-309
        • Venkatramani R.
        • Shoureshi P.
        • Malvar J.
        • Zhou S.
        • Mascarenhas L.
        High dose alkylator therapy for extracranial malignant rhabdoid tumors in children.
        Pediatr. Blood Cancer. 2014; 61: 1357-1361